Relevance of vein wall thickness in Behcet's disease: A systematic review and meta-analysis.

OBJECTIVES: To perform a meta-analysis on articles evaluating the common femoral vein wall thickness (VWT) in Behcet's disease and its possible clinical, laboratory and treatment correlates (BD). METHODS: Systematic search of EMBASE and PubMed databases from inception to October 2023; we employed random effect meta-analyses for continuous outcomes. RESULTS: The meta-analysis included 9 case-control and 1 cohort study: the VWT was greater in BD (n = 650) than in controls (n = 396) (p < 0.0001) with wide heterogeneity (I2 = 94.4%); a sensitivity analysis that included mean age of BD participants, gender, disease duration and activity, C-reactive protein, smoking status, immune-suppressive and anti-inflammatory medication, revealed that the heterogeneity variance was partly explained by age (p < 0.0001), male gender (p = 0.03), disease duration (p < 0.0001) and smoking (p = 0.06). The VWT was greater in BD with thrombotic/vascular (n = 189) than in non-thrombotic/vascular BD (n = 140) (p = 0.006) with no heterogeneity. CONCLUSION: VWT is greater in BD than controls: age, male gender, disease duration and smoking relate to VWT that was greater in BD patients with a history of thrombotic/vascular disease. Prospective studies are required to assess whether VWT may be considered a vascular marker of disease activity.

Biological therapy in systemic lupus erythematosus, antiphospholipid syndrome, and Sjögren's syndrome: evidence- and practice-based guidance.

Systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and Sjögren's syndrome (SS) are heterogeneous autoimmune diseases. Severe manifestations and refractory/intolerance to conventional immunosuppressants demand other options, namely biological drugs, and small molecules. We aimed to define evidence and practice-based guidance for the off-label use of biologics in SLE, APS, and SS. Recommendations were made by an independent expert panel, following a comprehensive literature review and two consensus rounds. The panel included 17 internal medicine experts with recognized practice in autoimmune disease management. The literature review was systematic from 2014 until 2019 and later updated by cross-reference checking and experts' input until 2021. Preliminary recommendations were drafted by working groups for each disease. A revision meeting with all experts anticipated the consensus meeting held in June 2021. All experts voted (agree, disagree, neither agree nor disagree) during two rounds, and recommendations with at least 75% agreement were approved. A total of 32 final recommendations (20 for SLE treatment, 5 for APS, and 7 for SS) were approved by the experts. These recommendations consider organ involvement, manifestations, severity, and response to previous treatments. In these three autoimmune diseases, most recommendations refer to rituximab, which aligns with the higher number of studies and clinical experience with this biological agent. Belimumab sequential treatment after rituximab may also be used in severe cases of SLE and SS. Second-line therapy with baricitinib, bortezomib, eculizumab, secukinumab, or tocilizumab can be considered in SLE-specific manifestations. These evidence and practice-based recommendations may support treatment decision and, ultimately, improve the outcome of patients living with SLE, APS, or SS.

Status Epilepticus in an Internal Medicine Ward: Different Patients Therefore Distinct Approaches.

Background Status epilepticus (SE) is a medical condition that bestows substantial morbidity and mortality. Literature is scarce regarding SE in elderly patients, particularly in the context of internal medicine wards. Aim To characterize SE patients admitted to an internal medicine ward, identify potential outcome predictors and differences between young and elderly, as well as convulsive (CSE) and non-convulsive SE (NCSE) patients. Methods We enrolled 135 consecutive patients in an observational, retrospective cohort study. We established elderly patients as more than 64 years old and defined worse prognosis as a modified Rankin Scale (mRS)>4. Results The SE population was 73% elderly, and 75% presented with NCSE, mainly metabolic, idiopathic, or vascular SE. The intra-hospital mortality was 51%, and 62% had an mRS>4 at discharge. NCSE and electroencephalogram (EEG) with paroxysmal activity at discharge were predictive of a worse prognosis. Elderly patients had increased disability at admission, most had NCSE (81%), and the SE etiology differed with more idiopathic and vascular causes. In the elderly, mortality was increased, as was the number of patients with mRS>4 at discharge. NCSE patients had the more neurodegenerative disease (30%) and presented predominantly with vascular and anoxic causes. Morbidity and mortality were also increased in the NCSE group. There was no difference in the antiepileptic drugs used or in the percentage of patients achieving an EEG with no paroxysmal activity between the subpopulations. Conclusion SE in elderly patients should be addressed distinctly. Current approaches based on the strategies used for standard CSE have shown little or no efficacy overall.

When a Histologic Diagnosis Becomes Factitious: A Case of Munchausen Syndrome.

Recurrent episodes of hypoglycemia are uncommon in non-diabetic patients. The workup investigation must confirm hypoglycemia and distinguish between endogenous versus exogenous hyperinsulinism. Simultaneous measurements of plasma glucose, insulin, C-peptide, and a screen for oral hypoglycemic agents should be performed. According to the results, further imaging studies may be necessary. A 43-year-old woman suffering from recurrent hypoglycemia presented to the emergency room (ER) with a hypoglycemic coma. She has had multiple episodes of documented hypoglycemia for the last 13 years. The case was initially investigated, and laboratory studies revealed endogenous hyperinsulinism. Screening for sulfonylureas, anti-insulin and anti-insulin receptor antibodies were negative. Body imaging and positron emission tomography (PET) with 68Ga-DOTANOC did not show evidence of an insulinoma. The patient was submitted to a pancreatectomy, which revealed nesidioblastosis in the histologic examination. Since then, the patient became hyperglycemic but the insulin doses were progressively reduced until new episodes of hypoglycemia recurred and the insulin was stopped. Again, inappropriately high levels of insulin were found at the time of hypoglycemic episodes. Computed tomography (CT) and PET scans did not find evidence of an insulinoma. A C-peptide was later found to be negative and insulin ampoules were found in her possession, making a diagnosis of a factitious disorder. Although rare, factious disorders are frequently overlooked and challenging to diagnose. Since they are very resource and time-consuming, self-inflicted illnesses should always be considered and ruled out beforehand.

Saliva molecular testing bypassing RNA extraction is suitable for monitoring and diagnosing SARS-CoV-2 infection in children.

BACKGROUND: Adults are being vaccinated against SARS-CoV-2 worldwide, but the longitudinal protection of these vaccines is uncertain, given the ongoing appearance of SARS-CoV-2 variants. Children remain largely unvaccinated and are susceptible to infection, with studies reporting that they actively transmit the virus even when asymptomatic, thus affecting the community. METHODS: We investigated if saliva is an effective sample for detecting SARS-CoV-2 RNA and antibodies in children, and associated viral RNA levels to infectivity. For that, we used a saliva-based SARS-CoV-2 RT-qPCR test, preceded or not by RNA extraction, in 85 children aged 10 years and under, admitted to the hospital regardless of COVID-19 symptomatology. Amongst these, 29 (63.0%) presented at least one COVID-19 symptom, 46 (54.1%) were positive for SARS-CoV-2 infection, 28 (32.9%) were under the age of 1, and the mean (SD) age was 3.8 (3.4) years. Saliva samples were collected up to 48 h after a nasopharyngeal swab-RT-qPCR test. RESULTS: In children aged 10 years and under, the sensitivity, specificity, and accuracy of saliva-RT-qPCR tests compared to NP swab-RT-qPCR were, respectively, 84.8% (71.8%-92.4%), 100% (91.0%-100%), and 91.8% (84.0%-96.6%) with RNA extraction, and 81.8% (68.0%-90.5%), 100% (91.0%-100%), and 90.4% (82.1%-95.0%) without RNA extraction. Rescue of infectious particles from saliva was limited to CT values below 26. In addition, we found significant IgM positive responses to SARS-CoV-2 in children positive for SARS-CoV-2 by NP swab and negative by saliva compared to other groups, indicating late infection onset (>7-10 days). CONCLUSIONS: Saliva is a suitable sample type for diagnosing children aged 10 years and under, including infants aged <1 year, even bypassing RNA extraction methods. Importantly, the detected viral RNA levels were significantly above the infectivity threshold in several samples. Further investigation is required to correlate SARS-CoV-2 RNA levels to viral transmission.

Morbimortality and Six-Month Survival Among Elderly Patients Treated With Noninvasive Mechanical Ventilation in an Intermediate Care Unit: A Retrospective Evaluation.

BACKGROUND: Noninvasive mechanical ventilation (NIMV) has been established as a successful therapeutic option for patients with acute respiratory failure (ARF) with a specific etiology. OBJECTIVES: This study evaluated the morbimortality of patients with ARF treated with NIMV in a medical intermediate care unit (UCINT) to identify factors associated with higher in-hospital mortality, six-month mortality, and three- and six-month hospital readmission rates. METHODS: This retrospective cohort study included elderly patients admitted for ARF and treated with NIMV in the UCINT between 2015 and 2019. RESULTS: In the sample of 102 patients, the median age was 84.2 (±5.5) years, and 57% were women. In total, 28% were on long-term oxygen therapy, and 68% had a do-not-resuscitate order. At admission, the median Charlson comorbidity index and Barthel index of activities of daily living were 7 [6; 8] and 30 [20; 57,5], respectively. The simplified acute physiology score II was 39.1±10.7, and 92% of patients had type 2 ARF. Median days on NIMV and days in UCINT were 10 [6; 16] and 6 [3; 10], respectively. The main conditions requiring UCINT admission for NIMV were heart failure, pneumonia, and exacerbation of the chronic obstructive pulmonary disease. The NIMV failure rate was 7%. At discharge, the average Barthel index was 35 [10; 55]. The in-hospital mortality rate was 23%. DISCUSSION:  Older age, higher simplified acute physiology score II, higher Charlson comorbidity index, and higher number of days on NIMV were associated with higher in-hospital mortality. Long-term oxygen therapy was associated with higher three-month mortality. A higher Barthel index at the time of hospital discharge was associated with a higher six-month readmission rate. CONCLUSION: NIMV can be used successfully in elderly patients and less studied ARF etiologies, such as pneumonia.

The role of the Notch pathway in the pathogenesis of systemic sclerosis: clinical implications.

INTRODUCTION: Systemic sclerosis (SSc) is a chronic debilitating disease characterized by vascular insufficiency, widespread fibrosis and immune activation. Current understanding of its pathophysiology remains incomplete, which translates into inefficient therapies. Notch signaling is a central player in the development of physiological and pathological fibrosis not only in general but also in the context of SSc and is most likely involved in the vascular dysfunction that characterizes the disease. AREAS COVERED: This review explores the role of the Notch pathway in the pathophysiology of SSc and the potential implications for the diagnosis, evaluation, and management of this yet incurable disease. EXPERT OPINION: Although major issues still exist about the comprehension of SSc and the design of effective treatments, the knowledge of the role of the Notch pathway in fibrogenesis and vascular biology has shed light and enthusiasm over the field. Drugs that target components of Notch signaling are currently in development including already some in clinical trials. As such, Notch may become a very important topic in the near future (considering both the pathophysiology and treatment perspectives), not only in the context of SSc but also in the vascular-dependent fibrotic processes present in a multitude of diseases.

Copper-induced Haemolytic Anaemia.

Acute copper toxicity is uncommon in Western countries and is often the result of accidental consumption or a suicide attempt. We report the case of a 65-year-old man presenting to the accident and emergency department after a suicide attempt with ingestion of Bordeaux mixture, ibuprofen, acetaminophen and bleach. Primary evaluation showed caustic oesophagitis, toxic hepatitis and acute renal injury, which were treated with supportive care. During admission, he developed a non-immune haemolytic anaemia associated with high levels of copper in urine and blood. Chelation treatment with penicillamine was started and evolution was favourable after 1 month of treatment. Copper poisoning can be lethal. Prompt diagnosis and treatment are key for a favourable prognosis. LEARNING POINTS: Acute copper intoxication is rare and early clinical suspicion and diagnosis are essential to reduce mortality.The diagnosis of copper poisoning should be based on clinical presentation and measurement of urine and blood copper levels in addition to serum ceruloplasmin levels.Treatment includes reduction of absorption, supportive measures, management of complications and chelation therapy.

Muscle Infarction Following Rapid Glycemic Control in a Patient With Diabetes-Associated Microvascular Disease.

We report a case of a 40-year-old African male with a history of diabetes mellitus with multiple microvascular complications, having recently initiated insulin treatment with a rapid decline in glycosylated hemoglobin (HbA1c) concentration. The patient presented with a sudden onset of right thigh pain and swelling not associated with trauma. Blood work revealed elevated inflammatory markers. A presumptive diagnosis of pyomyositis was made and the patient was treated with intravenous antibiotics with no improvement. Diabetic muscle infarction was then considered and confirmed by magnetic resonance imaging of the affected thigh. As with retinopathy and neuropathy deterioration that have been described as secondary to an aggressive glycemic control, it is possible that muscle myonecrosis may have been consequent to the rapid HbA1c normalization.

The role of high-density lipoprotein in the regulation of the immune response: implications for atherosclerosis and autoimmunity.

Inflammation and immune dysfunction have been increasingly recognized as crucial mechanisms in atherogenesis. Modifications in cell lipid metabolism, plasma dyslipidaemia and particularly low high-density lipoprotein (HDL) levels occur both in atherosclerosis and in autoimmune rheumatic diseases (which are strongly associated with an increased risk of atherosclerosis), suggesting the presence of a crucial link. HDL, the plasma lipoprotein responsible for reverse cholesterol transport, is known for its several protective effects in the context of atherosclerosis. Among these, HDL immunomodulatory effects are possibly the less understood. Through the efflux of cholesterol from plasma cell membranes with the consequent disruption of lipid rafts and the interaction with the cholesterol transporters present in the plasma membrane, HDL affects both the innate and adaptive immune responses. Animal and human studies have demonstrated a predominance of HDL anti-inflammatory effects, despite some pro-inflammatory actions having also been reported. The HDL role on the modulation of the immune response is further suggested by the detection of low levels together with a dysfunctional HDL in patients with autoimmune diseases. Here, we review the current knowledge of the immune mechanisms of atherosclerosis and the modulatory effects HDL may have on them.

Sensorineural Hearing Loss and Systemic Autoimmune Disease: The Experience of a Systemic Immune-Mediated Diseases Unit.

Background Autoimmune inner ear disease (AIED) represents less than 1% of all cases of sensorineural hearing loss (SNHL) but its frequency may be underestimated due to lack of specific clinical and laboratory criteria. AIED can be associated with a systemic autoimmune disease (SAID) in 15%-30% of the cases. The objective of the present study was to characterize the clinical and prognostic factors of a cohort of patients with AIED. Materials and methods The authors conducted a retrospective descriptive analysis of a cohort of patients with AIED referred from the otorhinolaryngology department to a systemic immune-mediated diseases unit between March 2013 and November 2020. A consecutive sample of 39 patients with suspected AIED was referred. SNHL was defined as a fall of the hearing threshold of at least 30 decibels in three consecutive frequencies. Eight patients were excluded for not meeting the audiometric criteria or having confounding factors. The remaining 31 patients were included with a total of 50 affected ears. To classify the intensity of hearing loss, an arithmetic mean of pure tone was calculated. Normal hearing or mild hearing loss at the last pure tone audiometry of the follow-up were an indicator of good prognosis and were considered the outcome of interest. Results Thirty-two percent of the patients had an associated SAID. There were no differences regarding demographic and clinical characteristics when comparing patients with AIED alone and patients with AIED and a SAID, except for the positivity of antinuclear antibodies (ANA). ANA positivity was superior in patients with the association of AIED and a SAID when compared with patients with AIED alone (90% vs 50%; p=0.037). The SAID was diagnosed after the AIED in 70% of the patients, in which diagnosis of the SAID occurred a median of 4,2 (IQR 0.8-5.1) years after the diagnosis of the AIED. Normal audiometric evaluation or a mild hearing loss was achieved in 31% of the ears at the last audiometric evaluation. A normal audiometry or a mild hearing loss at the time of diagnosis was independently associated with a better outcome (31%, 14%, CI 1.71-273.69; p=0.018). Bilateral hearing loss was independently associated with a worse outcome (54%, 79%, CI 0.01-0.84; p=0.035). The use of systemic corticosteroids (p=0.941), transtympanic corticosteroids (p=0.700) and non-steroid immunomodulator drugs (p=0.986) did not affect prognosis. The presence of a SIAD did not affect the prognosis (p=0.986). Conclusions In this cohort, SAID was present in one-third of the patients with AIED. A good prognosis was achieved in one-third of the patients. A normal audiometry or mild disease at presentation was associated with a good outcome, whilst bilateral involvement was associated with a bad one. Association of a SAID did not seem to influence the hearing-related prognosis. Positivity of ANA antibodies may justify performing a complementary investigation to determine the presence of a SAID.

Native Valve Aspergillus Endocarditis in a Non-Neutropenic Immunocompromised Patient on Anti-TNF α Blockers Therapy.

Invasive aspergillosis is a rare opportunistic infection mainly occurring in patients with a well-established risk such as neutropenia or conditions that lead to chronically impaired cellular immune responses. Systemic corticosteroids are a well-known risk factor for fungal infections. Recently, reports of invasive aspergillosis in patients treated with monoclonal biologic agents, such as tumor necrosis factor-alpha inhibitors, have been increasing. We present the case of a 47-year-old female patient with seronegative spondyloarthropathy treated with infliximab and corticosteroids. The patient presented classical symptoms of an acute lower respiratory infection, and she was treated with a ß-lactam antibiotic. Infliximab administration was deferred until nine days after clinical recovery. Fourteen days after drug administration, she was admitted with a symptomatic subcortical hematoma in the left parietal region. There was a rapid neurological recovery, and there were no risk factors for haemorrhagic stroke detected. The chest X-ray revealed an oval mass with an air crescent sign, and the CT scan was suggestive of aspergilloma. Bronchoalveolar lavage cytology identified Aspergillus spp. Voriconazole was initiated and, after one month of treatment, the patient was readmitted with a left facial palsy associated with hemiparesis and dysarthria. Laboratory evaluation showed leukocytosis and elevated C-reactive protein. A severe right middle cerebral artery stroke was present on the brain CT scan. Transesophageal echocardiogram revealed large mitral valve vegetation, and the diagnosis of Aspergillus endocarditis with cerebral embolization was made. Fungal infections are challenging due to the diagnosis infrequency and paucisymptomatic natural history. Despite being crucial in the treatment of autoimmune diseases, immunosuppressive drugs increase the risk of fungal infection. It is extremely important to consider Aspergillus infection in immunosuppressed patients, and the need for prophylaxis in non-neutropenic patients with risk factors should be clarified.

Changes in Iron Metabolism Induced by Anti-Interleukin-6 Receptor Monoclonal Antibody are Associated with an Increased Risk of Infection.

(1) Background: Treatment of patients with rheumatoid arthritis (RA) with an anti-IL-6 receptor (anti-IL-6R) monoclonal antibody (tocilizumab) has been found to influence iron metabolism. The objective of the present study was to ascertain whether changes in iron metabolism induced by anti-IL-6R biologic therapy were independently associated with an increased infection risk. (2) Methods: A prospective longitudinal study of patients with RA treated with tocilizumab was conducted. RA patients treated with an antitumor necrosis factor α monoclonal antibody were also included as a control group. The primary outcome was occurrence of infection during the first 24 months of biologic therapy. (3) Results: A total of 15 patients were included, with a mean age of 51.0 ± 4,1 and 73.3% (n = 11) female. A multivariate survival regression model, adjusted for confounding factors, was fitted for each of the iron metabolism variables. Hazard ratios for being above the median of each parameter was considered. Transferrin saturation above the median value (>32.1%) was associated with a higher infection risk (HR 4.3; 95%CI 1.0-19.69; p = 0.05). Similarly, although non-significantly, higher serum iron was strongly associated with infection occurrence. (4) Conclusions: This study identified a probable association between infection risk and higher serum iron and transferrin saturation in patients with RA on anti-IL-6R biologic therapy. We suggest that both these parameters should be considered relevant contributing factors for infection occurrence in patients on anti-IL-6R therapy.

ELISA methods comparison for the detection of auto-antibodies against apolipoprotein A1.

BACKGROUND: Autoantibodies against apolipoprotein A1 (anti-apoA1 IgG) have emerged as an independent biomarker for cardiovascular disease and mortality. Across studies, different ELISA methods have been used to measure the level of circulating anti-apoA1 IgG which could lead to substantial result differences between assays. OBJECTIVES: To make a comparative study of available anti-apoA1 IgG detection methods and to determine whether the choice of matrix sample (serum vs plasma) could influence the results. METHODS: Blood samples were obtained from 160 healthy blood donors and collected on 4 different matrixes (serum, plasma-EDTA, -citrate, -lithium-heparinate). Anti-apoA1 IgG was measured using two homemade (Geneva's and Lisbon's) and one commercial ELISA kits. Passing-Bablok and Bland-Altman were used to compare the results. Anti-apoA1 IgG seropositivity cut-offs were defined according to the user's/manufacturer's criterion. RESULTS: The current results showed substantial differences between those 3 assays. The dynamic ranges were significantly different, the commercial kit displaying the narrowest one. Passing-Bablok analysis demonstrated important proportional and constant biases between assays. The anti-apoA1 IgG seropositivity rate in Geneva, Lisbon and commercial assays varied between 24.5% and 1.9%. Matrix comparisons demonstrated that the matrix choice (plasma versus serum) influenced anti-apoA1 IgG results as well as the seropositivity rate in an assay-dependent manner. The coating antigen source was identified as important factor underlying results heterogeneity across assays. CONCLUSIONS: These results highlight the impact of the method and the cut-off used on anti-apoA1 IgG results and emphasize the need of standardizing existing assays. Given the important matrix influence, we suggest to use serum as matrix of choice.

Antiphospholipid antibodies and renal transplant: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of antiphospholipid antibodies (aPL) on renal allograft outcome after kidney transplantation. METHODS: A systematic search of EMBASE and PubMed databases from inception to July 2018 was run according to PRISMA guidelines; Peto's odds ratio (OR) for rare events was used for the meta-analysis. RESULTS: Our inclusion/exclusion criteria were met by 22 cohort studies having different outcomes: allograft thrombosis (n = 9) and thromboprophylaxis (n = 3), allograft loss from any cause (n = 9), allograft malfunction (n = 3), duration (n = 2), glomerular filtration rate at 1 year (n = 3) and allograft rejection (n = 5). The pooled prevalence of allograft thrombosis and of thrombotic microangiopathy was greater in aPL+ve than negative recipients (10.4% vs 1.7%, p < 0.0001 and 10.2% vs 0%, p = 0.005, respectively). The pooled prevalence of allograft thrombosis was 75% in patients not taking anticoagulation whereas none of the anticoagulated recipients developed thrombosis (p < 0.0001). The pooled prevalence of allograft loss was greater in aPL+ve recipients (28% vs 18% respectively, p < 0.0001); the pooled prevalence of aPL was greater in allograft loss recipients compared to those who did not lose it (51% vs 33%, p < 0.0001). The pooled prevalence of allograft malfunction and rejection was similar in aPL-ve and aPL+ve recipients (32.2% vs 40.3% and 14.9% vs 14.4%, respectively) but graft duration was shorter in aPL+ve than aPL-ve recipients (p = 0.001) and glomerular filtration rate at 1 year was lower in aPL + ve than aPL-ve recipients (p < 0.0001). CONCLUSION: APL relate strongly to allograft thrombosis, loss and duration but not to allograft malfunction and rejection. Oral antivitamin K anticoagulants effectively prevent allograft thrombosis in aPL recipients. The debate on the role of aPL in renal transplant is limited by the expression of data as percentage of recipients positive for aPL rather than aPL titres in many studies.

Psoriasis-associated vascular disease: the role of HDL.

Psoriasis is a chronic inflammatory systemic disease with a prevalence of 2-3%. Overwhelming evidence show an epidemiological association between psoriasis, cardiovascular disease and atherosclerosis. Cardiovascular disease is the most frequent cause of death in patients with severe psoriasis. Several cardiovascular disease classical risk factors are also increased in psoriasis but the psoriasis-associated risk persists after adjusting for other risk factors.Investigation has focused on finding explanations for these epidemiological data. Several studies have demonstrated significant lipid metabolism and HDL composition and function alterations in psoriatic patients. Altered HDL function is clearly one of the mechanisms involved, as these particles are of the utmost importance in atherosclerosis defense. Recent data indicate that biologic therapy can reverse both structural and functional HDL alterations in psoriasis, reinforcing their therapeutic potential.

Extended-release niacin increases anti-apolipoprotein A-I antibodies that block the antioxidant effect of high-density lipoprotein-cholesterol: the EXPLORE clinical trial.

AIMS: Extended-release niacin (ERN) is the most effective agent for increasing high-density lipoprotein-cholesterol (HDL-C). Having previously identified anti-HDL antibodies, we investigated whether ERN affected the antioxidant capacity of HDL and whether ERN was associated with the production of antibodies against HDL (aHDL) and apolipoprotein A-I (aApoA-I). METHODS: Twenty-one patients older than 18 years, with HDL-C ≤40 mg dl-1 (men) or ≤50 mg dl-1 (women) were randomly assigned to receive daily ERN (n = 10) or placebo (n = 11) for two sequential 12-week periods, with 4 weeks of wash-out before cross-over. Primary outcome was change of paraoxonase-1 (PON1) activity and secondary outcomes were changes in aHDL and aApoA-I antibodies. Clinical Trial Unique Identifier: EudraCT 2006-006889-42. RESULTS: The effect of ERN on PON1 activity was nonsignificant (coefficient estimate 20.83 U l-1 , 95% confidence interval [CI] -9.88 to 51.53; P = 0.184). ERN was associated with an increase in HDL-C levels (coefficient estimate 5.21 mg dl-1 , 95% CI 1.16 to 9.25; P = 0.012) and its subclasses HDL2 (coefficient estimate 2.46 mg dl-1 , 95% CI 0.57 to 4.34; P = 0.011) and HDL3 (coefficient estimate 2.73 mg dl-1 , 95% CI 0.47 to 4.98; P = 0.018). ERN was significantly associated with the production of aApoA-I antibodies (coefficient estimate 0.25 µg ml-1 , 95% CI 0.09-0.40; P = 0.001). aApoA-I titres at baseline were correlated with decreased PON activity. CONCLUSIONS: The rise in HDL-C achieved with ERN was not matched by improved antioxidant capacity, eventually hampered by the emergence of aApoA-I antibodies. These results may explain why Niacin and other lipid lowering agents fail to reduce cardiovascular risk.